JPH0222246A - Production of alkali phenylpyruvate - Google Patents

Abstract

PURPOSE: To obtain the title substance by bringing a Ca(OH)₂ suspension in a water/isopropanol mixed soln. into contact with NaS, Na thiosulfate, cobalt chloride and CO and introducing benzyl chloride into the mixed soln. to filter Ca phenylpyruvate to treat the same with a base.

CONSTITUTION: A Ca(OH)₂ suspension (1) in a water/isopropanol mixed soln. (2) is brought into contact with NaS (3), sodium thiosulfate (4), cobalt chloride (5) and CO (6) and benzyl chloride (7) is introduced into the mixed soln. to hold the resulting mixture under pressure (5-30 bar) of CO (6) and Co is oxidized by 10% sodium hypochlorite (8). Subsequently, the reaction mixture is filtered under weak pressure by using a belt filter and the obtained residue is washed with a water/isopropanol mixed soln. (9). Calcium phenylpyruvate is introduced into an org. solvent not mixed with water along with an aq. hydrochloric acid soln. (12) and phenylpyruvate is separated from a Co salt aq. soln. 14 by gradient separation and changed to a salt by an alkali aq. soln. (15) to obtain the title substance as an aq. soln. 16 by gradient separation.

COPYRIGHT: (C)1990,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new process for the preparation of alkali phenylpyruvate salts by double carbonylation of benzyl chloride, and more particularly to an industrial process for the preparation of this product.

The production of phenylpyruvic acid by double carbonylation of benzyl chloride has been known for some time.

For example, US Pat. No. 4,152,352 describes a process for the double carboxylation of benzyl chloride in the presence of a base, especially an alkaline earth base, and a cobalt carbonyl-based catalyst in a water/alcoholic solvent.

The preparation of catalysts which are salts of cobalt tetracarbonyl is described in detail in European Patent Box 108,698. According to this patent, a sulfur derivative or a mixture thereof is contacted with cobalt dichloride together with an alkaline earth base, preferably lime, in a medium consisting of water and/or alcohol.

The combination of these two patents describes the production of a catalyst that unfortunately must be stored and then used in double carbonylation, but both patents are easy to perform and provide high yields. does not describe a combined reaction of the carbonylation of benzyl chloride with the preparation of a catalyst that allows calcium phenylpyruvate to be obtained in a single reaction by a good method.

This reaction, simple in principle, poses many problems in implementation. In fact, on the one hand, the reaction medium comprises three phases: solid, liquid and gas phase, which requires appropriate techniques in terms of stirring and displacement, and on the other hand, it is necessary that the reaction rate be fast. Furthermore, recovery of phenylpyruvate is extremely complex. This is because it is extremely difficult to separate this product from the complex reaction medium containing inorganic salts, organic substances, solvents and water.

The resulting calcium phenylpyruvate is a brittle product that cannot be heated as it may decompose; its physical form is needle-like crystals that break easily; it cannot be distilled; It cannot be extracted purely with solvents. Filtration is the only advantageous industrial technique that can separate. The filtration follows the manufacturing conditions of phenylpyruvate, thus resulting in double carbonylation,
It depends on the physical and chemical qualities that characterize the product.

Secondary products, i.e. solvents, inorganic salts, are economically
It needs to be recovered or removed, depending on practicable methods, or taking into account environmental safety standards.

The resulting calcium phenylpyruvate needs to undergo a conversion reaction to obtain an alkali phenylpyruvate salt which can be used as an intermediate in the pharmaceutical or agrochemical industry.

The main use of alkali phenylpyruvate is in the production of phenylalanine.

This synthesis is advantageously carried out by enzymatic transamination, as described in the example of US Pat. No. 4,600,692. All enzymatic reactions are favorable to the purity of the raw material, which governs the purity of the alkali phenylpyruvate.

A combination of these problems is solved by the method of the present invention.

The object of the present invention was achieved by obtaining a reaction solution in which calcium phenylpyruvate could be separated by filtration and then converting this calcium salt into an alkali salt of phenylpyruvate.

In the first step, the present invention combines calcium hydroxide suspension (1) in water/isopropanol mixture (2) with sodium sulfide (3), sodium thiosulfate (4), and cobalt chloride (5). and - in contact with carbon oxide (6); in a second step, benzyl chloride (7) is introduced into the mixture obtained in the first step and the reactor is kept under pressure with carbon monoxide (6); , in the third step, oxidize the cobalt directly in the product of the second step, and in the fourth step, filter the calcium phenylpyruvate through a thin filter bed, acidify the filtrate, and then oxidize the isopropanol/ The aqueous azeotrope is distilled and returned to the first step 2, the cobalt and calcium salts are returned to the aqueous solution, and in the fifth step calcium phenylpyruvate is
Drying at a temperature of 0° C. or lower to remove isopropazole; in the sixth step, acidify the calcium phenylpyruvate suspended in an organic solvent that is immiscible with water, and perform gradient separation of phenylpyruvate; and in the seventh step In 2 to 8, the method for producing an alkali phenylpyruvic acid salt is directed to neutralizing pyruvic acid with an alkaline base.

EP 108,698 does not specify the preparation of a double carbonylation catalyst in which the carbonylation catalyst is prepared in a carbonylation reactor and benzyl chloride is added directly in this reactor.

The disclosure of this patent makes it possible to avoid pre-preparing, storing and handling the catalyst in a separate reactor. It must be remembered that calcium cobalt tetracarbonyl is a non-volatile hazardous substance, and when converted to cobalt tetracarbonyl hydride, it produces highly toxic volatile substances. The advantage of using only a single reactor is due to the economical design. This is because it eliminates the sequential pressurization of two reactors with carbon monoxide.

Filtration, which was previously a problem depending on the properties of calcium phenylpyruvate, could be solved by stirring by various chemical or engineering means.

From a chemical point of view, we have found that the concentration of cobalt in the reaction solution should be as low as possible in order to facilitate the filtration of calcium phenylpyruvate. It is most desirable that the concentration of the cobalt catalyst in every liter of the reaction solution be about 10@-3 mol. 10-3 to 5X10- per reaction solution 12
``It is preferred to use molar concentrations.

By reducing the concentration of cobalt tetracarbonyl in this way, correct reaction rates can be maintained in industrial programs. Carbonylation with such small amounts of catalyst has not been described in the prior literature.

From an industrial point of view, the stirring system influences the filterability. The larger the phenylpyruvate crystals, the easier it is to filter. Similarly, the stirring system needs to have good contact between the gas and the liquid, but it also needs to minimize the destruction of crystals. The system used in the present invention is coupled with a gas circulator that circulates the gas phase within the reactor into the reaction medium.
Consists of stirring blades that require little force for stirring.

Solvents also play an important role in filterability. Alcohol is preferred for filterability and selectivity, and water is preferred for reaction rate. A good balance between reaction rate and filterability was achieved with a water/isopropanol mixture containing about 80 volumes of isopropanol per 20 volumes of water.

In a preferred embodiment of the invention, the molar concentration of cobalt is between 10 and 5 x 10 atomic grams per reaction medium 12, the amount of calcium hydroxide corresponds to the stoichiometry of the reaction, and the concentration of sulfur derivatives is is between 0.01 and 1, preferably about 0.2, per atomic gram of cobalt. It is preferred to react with a molar ratio of cobalt-based catalyst to benzyl chloride of io-' to 1o-2. Carbon monoxide is advantageously used at a pressure of 5 to 30 bar.

In particular, it is effective to carry out the double carbonylation at a temperature of 60 to 90°C.

Before filtering the reaction medium, it is preferred to convert all cobalt in the oxidation state (-1) to cobal I-(+2), rendering it harmless.

This oxidation step is preferably carried out in the presence of sodium hypochlorite.

To carry out the oxidation, a 10% aqueous sodium hypochlorite solution (
8) is preferably used. It is particularly preferred that this solution is introduced into the warm crude reaction medium, preferably about 60°C.

The suspension thus obtained is no longer in the oxidized state (-1)
(7) It does not contain cobalt, and its rheology does not change with respect to the suspension produced by the reaction.

If the cobalt is not oxidized, the reaction composition will exhibit a respective change.

In the fourth step, for example with a belt filter or with any filter device that does not result in too thick a filter cake,
Filter under gentle pressure. It is preferable to perform filtration at a temperature of about 60°C. The filter residue is washed with a water/isopropanol mixture (9) having properties similar to those used in the double carbonylation, in particular containing 1 volume of water to 1 volume of isopropanol. Washing is preferably carried out by elution, displacing only a thin layer of the original solution without creating turbulence either at the solid or liquid level.

The isopropanol/water azeotrope contained in the filtrate is distilled and recycled after acidifying the filtrate.

This acidification is carried out, for example, with hydrochloric acid or sulfuric acid until the pH is about 3. The acid, a reaction by-product of acidification, is liberated from its calcium salt (11). Although this acid is an oily fluid, it does not interfere with azeotropic distillation or clog the distillation column.

The filtration residue is dried in the fifth step to remove the solvent kept at 80° C. or lower. In order not to deteriorate the calcium phenylpyruvate, it is preferable to leave a small amount of residual water, the amount of which is advantageously between 5 and 20% by weight.

The calcium phenylpyruvate obtained in the fifth step is acidified to liberate the phenylpyruvic acid into the organic solution and the salts, especially cobalt chloride and calcium chloride, into the aqueous solution.

This acidification reaction is carried out under precise conditions so that the acid can be easily gradient separated. Calcium phenylpyruvate is introduced into a water-immiscible organic solvent together with an aqueous hydrochloric acid solution (12).

The organic solvent can be selected from the following solvents.

These are aliphatic or aromatic as shown below, and may be halogenated.

Chloroform Chlorinated methane benzene chloride toluene xylene.

The following ethers may also be used.

isopropyl ether ethyl ether Methyl tertiary butyl ether.

The following esters may also be used.

Ethyl acetate.

Among them, it is preferable to use methyl tertiary isobutyl ether.

The molar ratio of hydrochloric acid to filtrate crude calcium phenylpyruvate is between 2 and 8, preferably about 4.

The amount of calcium phenylpyruvate used is 0.1~
1 kg is preferred.

According to a further preferred method, it is advantageous to introduce the calcium phenylpyruvate into an emulsion of methyl tertiary isobutyl ether and hydrochloric acid. It should be noted that if too much water is added, solids will form which will interfere with the gradient separation and prevent phenylpyruvate from being separated. Moreover, when the amount of water is too small, phenylpyruvic acid deteriorates. The amount of water to solvent is preferably 1 to 3 by weight.

Phenylpyruvic acid in acidified solution in an organic solvent is
Gradient separation from the aqueous solution (14) containing inorganic salts, especially cobalt salts.

Phenylpyruvic acid in an organic solvent is dissolved in an alkaline aqueous solution (1
5) Change to salt. This is preferably carried out continuously, for example in a reactor equipped with a shear stirrer. The alkali is preferably a sodium carbonate solution.

't8? Advantageously, the pl+ of Fi is from 6 to 8, and the reaction time is preferably less than 1 hour. After conversion to the salt, the aqueous phenylpyruvate alkali salt solution (16) can be decanted from the water-immiscible organic solvent and introduced directly into the enzymatic transamination reaction.

The invention may be better understood by the following example. This example should not be considered as limiting the invention.

Phenylpyruvin Calcium PPCa) 1, Testing with Concentrated Catalyst Solutions Prepared in Situ In a stainless steel reactor with a capacity of 3.6 f equipped with stirring impellers and a gas circulator, Ca (Ko) = 222 g ( 3 mol) 1250 g of isopropanol and 311 g of water were successively introduced.

The suspension was stirred and purged three times with nitrogen at 5 bar pressure and then three times with CO at 5 bar pressure.

Next, C
Ca [Go (Co) containing 6×40-” moles of o-”
4-12 water/alcohol mixture) capacity? ! 29.6g
introduced.

The reactor was brought to 70° C. under a pressure of 19 bar CO;
250 g of benzyl chloride at 0.degree. C. were introduced over a period of 6 hours under a pressure of 19 bar CO.

The molar ratio of Co-' to warmed benzyl was 3X10-'.

At the end of the reaction, when almost no CO was absorbed, the reaction mixture was evacuated to a pressure of 1 bar and cooled to 60°C. The turbid liquid was filtered and the residue was 50150% by volume.
of water/isopropanol mixture.

During the filtration, a flow resistance α-0.4 m/kg was measured.

After drying, 438 g of dry filter cake containing 56.6% of phenylpyruvic acid was obtained. This is a yield of 77.4% based on the benzyl chloride used.

2. Test with preparation of catalyst in the reactor In the same apparatus as test 1, Ca(OH)z 222 g (3 mol) isopropanol 1240 g water 311 g CoCp,
z (10,87 mmol) Naz
S (0,95 mmol) Nat
SOz (0.87 mmol) was introduced sequentially.

The reactor was flushed three times with nitrogen at a pressure of 5 bar, then with a pressure of 5 bar.
of CO three times.

It was warmed to 75° C. under a pressure of 19 bar of CO and allowed to react for 45 minutes. The yield of the produced Ca [Co (Co) 4 ] was about 80%, and about 8 mmol of Co-' was obtained in solution. Then under pressure 245 g of benzyl chloride (1,9
37 mol) were introduced directly in 20 minutes. The molar ratio of Co-' to warmed benzyl was 4X10-'. After 5 hours, a selectivity of 75% for phenylpyruvic acid was obtained. This mixture was treated as in Test 1.

3. Treatment of filtrate Isopropanol 69 weight% 11□0 22 weight% CoCQ, 5 weight% organic matter
3.6% by weight. To 1 kg of filtrate with this composition, 38% H (J! 2
2.6g was added to give ptl=3. The acidified filtrate was continuously evaporated in a single stage distiller (P - atmospheric pressure, T steam - 80°C). The evaporation rate was 78%.

The distillate was an isopropanol/water azeotrope in a weight ratio of 85/15. The recovery rate of isopropanol was 99%.

The distillation residue was subjected to gradient separation into the following two phases.

Organic phase 47g Aqueous phase 174g The organic phase was distilled and the aqueous phase saturated with CoCfz was reused.

4. Sodium phenylpyruvate (P
(1) Acidification of l'Pcal'Pca 0.167 mol of dry calcium phenylpyruvate obtained under the above conditions was converted into methyl Tertiary isobutyl ether/H (1/
It was added to a suspension of II□O (300d10.67 mol/355g).

The temperature was kept at 20°C and purged with nitrogen for 1 hour.

The aqueous phase containing CaCl-z + CoCe z was decanted and 238.2 g of a light brown organic phase containing phenylpyruvic acid (to PP) was obtained, the yield of PPA/PPCa was 98%.

(2) Conversion of PPA to PPNa salt Ru5hton
500mj stirred by a stirring blade! An organic phase of phenylpyruvic acid was continuously introduced into the reactor at a rate of 200 d/h. In parallel, the reactor was purged with nitrogen for 20 minutes and a 1.086 weight ratio sodium carbonate solution was added continuously;
The pH was kept at 7.5.

After 4 hours of reaction, the yield of PPNa/PPA was 95%. The final aqueous phase contained 5% PPNa in water.

The organic phase of methyl tertiary isobutyl ether was returned directly to the acidification step.

[Brief explanation of the drawing]

The figure is a process diagram for carrying out the manufacturing method of the present invention. ■...Calcium hydroxide suspension, 2.9...Water/isopropanol mixture, 3...Sodium sulfide,...Thorium thiosulfate,...Kohal chloride]...1 Carbon oxide, ...benzyl chloride, ...sodium hypochlorite, ■...calcium salt, 2...hydrochloric acid aqueous solution, 4...cobalt salt aqueous solution, 5...alkaline aqueous solution, 6...・Phenylpyruvate aqueous solution.

Claims (1)

[Claims] 1. In the first step, a suspension of calcium hydroxide in a water/isopropanol mixture is contacted with sodium sulfide, sodium thiosulfate, cobalt chloride and carbon monoxide; in the second step, , introducing benzyl chloride into the mixture obtained in the first step and keeping the reactor under pressure of carbon monoxide, in the third step oxidizing the cobalt directly in the product of the second step, and in the fourth step In the process, after filtering the calcium phenylpyruvate through a thin filter bed and acidifying the filtrate, the isopropanol/water azeotrope is distilled, which is returned to the first step, and the cobalt and calcium salts are returned to the aqueous solution. , In the fifth step, calcium phenylpyruvate is added to 8
The isopropanol is removed by drying at a temperature of 0° C. or lower, and in the sixth step, the calcium phenylpyruvate suspended in an organic solvent that is immiscible with water is acidified, and the phenylpyruvic acid is separated by gradient, and the seventh step is performed. A method for producing an alkali salt of phenylpyruvate, which comprises neutralizing pyruvic acid with an alkaline base. 2. The method according to claim 1, wherein the cobalt concentration is 10^-^3 to 5 x 10^-^3 mol/l. 3. The ratio of moles of sulfur derivative to gram atoms of cobalt is 0.
．． 01-1. The method according to claim 1. 4. Process according to claim 1, characterized in that the molar ratio of cobalt-based catalyst to benzyl chloride is between 10^-^3 and 10^-^2. 5. Process according to claim 1, characterized in that carbon monoxide is used at a pressure of 5 to 30 bar. 6. The method according to claim 1, wherein the carbonylation reaction is carried out at a temperature of 60 to 90°C. 7. The method according to claim 1, wherein the oxidation in the third step is carried out by adding sodium hypochlorite. 8. Add sodium hypochlorite at a temperature of about 60°C.
The method according to claim 7. 9. The method according to claim 1, wherein the filtration in the fourth step is performed using a filter with a thin filter bed. 10. The method of claim 1, wherein the filtrate of the fourth step is acidified to pH=3. 11. The method according to claim 1, wherein in the sixth step, an aliphatic or aromatic hydrocarbon, or a halogenated hydrocarbon thereof, an ether, or an ester is used. 12. The method according to claim 1, wherein methyl tertiary isobutyl ether is selected and used as the solvent. 13. The method according to claim 1, wherein in the sixth step, the molar ratio of hydrochloric acid to phenylpyruvate acidified with a hydrochloric acid solution is 2 to 8.